A working group formed to consider the use of minimal residual disease (MRD) in the treatment of multiple myeloma and the development of new therapies has issued a call for additional regulatory guidance on the use of MRD as a marker in clinical trials.
 
The working group, a collaboration of advocacy organizations, patients, research foundations, academic, government agencies and industry, was initially convened in 2016 by the Foundation for the National Institutes of Health Biomarkers Consortium. The group issued its first white paper in 2017, focusing on the role of MRD in treatment selection and drug development.
 
In a new paper, published in Clinical Cancer Research, the group said that more trials would be able to employ MRD as an endpoint if regulatory agencies used existing data from completed multiple myeloma trials to develop guidance specifying the timepoints that prospective trials should employ for evaluating MRD status.
 
“Such guidance will of course evolve, but if we wait for future clinical trials to provide definitive validation of MRD as a surrogate endpoint, valuable years will be lost as we wait for these studies to progress and these data to mature. Often, novel drugs are most likely to benefit [multiple myeloma] patients in early lines more than in the late lines of treatment, where they are first evaluated, and the availability of MRD as a surrogate endpoint will expedite these clinical trials and their application,” wrote Kenneth C. Anderson, of Dana-Farber Cancer Institute in Boston, and his colleagues.
 
The US Food and Drug Administration (FDA) has issued guidance on the use of MRD in clinical trials conducted under an investigational new drug application (IND) or to support marketing approval of drugs and biological products. The guidance addresses assay considerations, the evidence required to support MRD as a surrogate endpoint, disease-specific considerations, and considerations for using MRD as a patient selection factor. (RELATED: FDA Finalizes 2018 Guidance on Use of Minimal Residual Disease, Regulatory Focus 24 January 2020).
 
FDA’s guidance, which was finalized in January 2020, notes that evidence to support use of MRD as a surrogate endpoint in trials depends on three factors: the biological plausibility of the relationship, demonstration in epidemiological studies of the prognostic value of the endpoint for clinical outcomes, and evidence from clinical trials that the treatment effects on the surrogate endpoint correspond to the effects on the clinical outcome. The first two elements – biological plausibility and prognostic value – have been supported in multiple studies, according to the working group authors. The missing piece is evidence from trials on the relationship between treatment effect on MRD and clinical outcomes, they wrote.
 
“There are current efforts to gather evidence from clinical trials to allow for further evaluation of the treatment effect relationship between MRD and clinical outcomes such as [progression-free survival] and [overall survival] on both a trial-level and at an individual patient-level,” wrote the authors. “These data will supplement our understanding of MRD and how to most effectively use MRD to expedite drug development.” 
 
The working group also highlighted a review of applications submitted to the FDA’s Division of Hematology Products between 2014 and 2016. Overall, nearly 40% of the applications submitted included MRD data, but nearly one-third of those applications containing MRD data were deemed “uninterpretable” by the agency.
 
“Regardless of the registrational intent for a trial, it is important that the trial is adequate to meet its stated objectives,” the working group wrote. “If MRD assessment is a key component of the trial objectives, the MRD assessment should provide interpretable data.”
 
The working group noted that for MRD to “function as an effective regulatory tool” it will need to be considered within the context of underlying disease, patient heterogeneity, therapeutic context, therapeutic target, or a combination of disease parameters.
 
“It is vitally important for the continuation and advancement of drug development in [multiple myeloma] that regulatory agencies and industry collaborate in the near-term to establish a faster, accepted, surrogate endpoint for the future treatment of [multiple myeloma] patients,” the working group wrote.
 
Minimal Residual Disease in Myeloma: Application for Clinical Care and New Drug Registration